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Repression of TNF-alpha-induced E-selectin expression by PPAR activators: involvement of transcriptional repressor
1Department of Biochemical Genetics, Faculty of Medicine, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
Abstract:
Peroxisome proliferator-activated receptor (PPAR) activators were shown to inhibit the expression of E-selectin of human vascular endothelial cells in response to tumor necrosis factor-alpha (TNF-alpha). Troglitazone, pioglitazone, alpha-clofibrate, and 15-deoxy-Delta12,14-prostaglandin J2 all inhibited the TNF-alpha-stimulated E-selectin gene transcription in reporter assay. To further clarify the underlying transcriptional regulation, nuclear factor(s) that binds to the nuclear factor-endothelial leukocyte adhesion molecule 1 (NF-ELAM1) site of the E-selectin gene promoter was investigated. The activators caused a significant induction of liver regenerating factor 1 (LRF1)/activating transcription factor 3 (ATF3), which bound to the NF-ELAM1 site and repressed the TNF-alpha-induced E-selectin gene expression. From these data, the effect of PPAR activators was mediated, in part, through the induction of LRF1/ATF3. This might provide a novel molecular mechanism of anti-inflammatory effect of PPAR activators.